PB2515: A PILOT STUDY OF THE INTERNATIONAL HEMOGLOBINOPATHY RESEARCH NETWORK (INHERENT)
Authors: Petros Kountouris, Coralea Stephanou, Maxwell Nwegbu, Obiageli Nnodu, Morohuntodun Oni, Natasha Archer, Leon Tshilolo, Bin Alwi Zilfalil, Kyriaki Michailidou, Viviana Giannuzzi, Fedele Bonifazi, Marina Kleanthous
Journal: HemaSphere (2023)

Topic: 26. Sickle cell disease Background: Hemoglobinopathies, including sickle cell disease (SCD) and thalassemia syndromes, represent the commonest monogenic diseases in the world. Although their pathogenesis is well established, the diverse clinical manifestations and the varying degree of severity of hemoglobinopathies are less understood and are thought to be governed, in part, by genetic modifiers. Despite the identification and characterization of a few genetic modifiers by previous studies, these are as yet insufficient to guide treatment recommendations or stratify patients reliably. Larger, multi-ethnic studies are needed to identify and validate further disease modifiers that can be used for patient stratification and personalized treatment. The International Hemoglobinopathy Research Network (INHERENT) has been recently established to investigate the role of genetic modifiers in hemoglobinopathies, through a large, multi-ethnic genome-wide association study (GWAS). Aims: This pilot study aims to test the operational feasibility of the INHERENT study in different geographic and healthcare settings, thus identifying potential challenges in performing the envisioned GWAS within the INHERENT network. Methods: INHERENT members participating in the pilot study have been selected based on their geographic location (Cyprus, DR Congo, Malaysia, Nigeria, USA), disease group distribution (SCD/thalassemia) and hemoglobinopathy-specific healthcare policy. Five healthcare providers participate in the pilot study aiming to enroll 500 patients with an inherited hemoglobinopathy worldwide. The following steps of the study implementation are tested: (a) local bioethics approval on the basis of the applicable local legal framework; (b) patient enrollment; (c) sample/data collection; (d) genotyping of globin genes; (e) centralized GWAS experiments; and (f) statistical analysis of GWAS data. Results: A survey was designed to understand the rules in different countries and sites and, therefore, allow a better preparation of the study material and data exchange across the network. The INHERENT study protocol has been developed to enable a common approach among all participating centers. A common case report form (CRF) has been also developed on REDCap to facilitate standardized collection of phenotypic data, which include data parameters related to demographics, laboratory measurements, clinical complications and treatment regimens. In addition, common experimental protocols have been developed for the GWAS experiments, including collection, storage, and transfer of samples, and for determining the α and β genotypes. Summary/Conclusion: The INHERENT pilot study will test common standards developed within the INHERENT network and will enable early identification of key challenges associated with the conduction of a large, multi-ethnic study for hemoglobinopathies. After addressing these challenges, INHERENT will scale up to the full network membership, which currently involves over 110 organizations spanning 45 countries worldwide. The large increase in the sample size and the diversity in the studied populations will enable novel discoveries and expand knowledge on hemoglobinopathy genetics, thus paving the way for advancing the science of personalized diagnosis and treatment Acknowledgements: The INHERENT pilot study was supported through a grant from Agios Pharmaceuticals Inc. Keywords: Sickle cell disease, Thalassemia, Genetic modifiers